Benzimidazoles that enhance the activity of oligonucleotides
This disclosure is directed to methods, compounds and compositions for delivering nucleic acids to a cell of interest. In particular, it provides salts that are particularly effective in delivering nucleic acids to cells in the lung for disorders such as cystic fibrosis (CF).
1. A compound having the Formula I:
wherein:
R 1 is a pyrrolidine group;
R 2 -R 5 are each independently C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, H or halogen;
n is an integer between 1 and 8;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein n is 2-4 and R 1 is a pyrrolidine group.
3. The compound of claim 1 , wherein n is 2-4 and R 2 -R 5 are each independently C 1-4 alkyl, C 1-4 alkoxy, H or halogen.
4. The compound of claim 3 , wherein the halogen is bromine or chorine.
5. A composition comprising the compound of claim 1 , wherein the composition further comprises a compound having the Formula II:
wherein:
R 8 is C 1-8 alkyl or a linking group;
R 9 is C 1-8 alkyl or a linking group;
R 10 is C 1-8 alkyl;
R 11 and R 12 are each independently aryl, C 1-8 alkyl, C 1-8 alkoxy, amino, H, halogen, or heteroaryl;
or a pharmaceutically acceptable salt thereof.
6. The composition of claim 5 , wherein the compound of Formula II has the structure:
or a pharmaceutically acceptable salt thereof.
7. A composition comprising an oligonucleotide and a compound having the Formula I:
wherein:
R 1 is a pyrrolidine group;
R 2 -R 5 are each independently C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, H or halogen;
n is an integer between 1 and 8; and
a pharmaceutically acceptable carrier.
8. The composition of claim 7 , wherein the composition further comprises a compound having the Formula II:
wherein:
R 8 is C 1-8 alkyl or a linking group;
R 9 is C 1-8 alkyl or a linking group;
R 10 is C 1-8 alkyl;
R 11 and R 12 are each independently aryl, C 1-8 alkyl, C 1-8 alkoxy, amino, H, halogen, or heteroaryl;
or a pharmaceutically acceptable salt thereof.
9. The composition of claim 8 , wherein the compound of Formula II has the structure:
or a pharmaceutically acceptable salt thereof.
10. The composition of claim 1 , wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer (PMO).
11. A method of administering an oligonucleotide of interest to a cell which comprises administering to the cell the oligonucleotide and a compound of Formula I:
wherein:
R 1 is a pyrrolidine group;
R 2 -R 5 are each independently C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 3-8 alkynyl, C 3-8 cycloalkyl, H or halogen;
n is an integer between 1 and 8;
or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 , further comprising administering to the cell a compound having the Formula II:
wherein:
R 8 is C 1-8 alkyl or a linking group;
R 9 is C 1-8 alkyl or a linking group;
R 10 is C 1-8 alkyl;
R 11 and Ria are each independently aryl, C 1-8 alkyl, C 1-8 alkoxy, amino, H, halogen, or heteroaryl;
or a pharmaceutically acceptable salt thereof.
13. The method of claim 11 , wherein the oligonucleotide is a phosphorodiamidate morpholino oligomer (PMO).
14. The method of claim 11 , wherein the method is carried out by administering the oligonucleotide to the cell, and concurrently administering the compound having formula I to the cell.
15. The method of claim 11 , wherein the compound having formula I is administered after the oligonucleotide is administered to the cell.
16. The method of claim 11 , wherein the oligonucleotide is an antisense oligonucleotide.
17. The method of claim 11 , wherein the oligonucleotide is a splice switching oligonucleotide.
18. The method of claim 11 , wherein the oligonucleotide is an siRNA.
19. The method of claim 11 , wherein the cell is a lung cell or an airway cell.
20. The method of claim 19 , wherein the lung cell is a human bronchial epithelial cell (HBEC), a human nasal epithelial cell (HNEC), a mouse tracheal epithelial cell (MTEC), a human alveolar type I or type II cell, a human lung submucosal gland cell, a human lung leucocyte, or a human lung inflammatory cell.
21. The compound of claim 1 , wherein the compound of Formula I has the structure:
22. The composition of claim 7 , wherein the compound of Formula I has the structure:
23. The method of claim 11 , wherein the compound of Formula I has the structure: